Abstract 17977: Serial Gene Expression Changes Associated With Reverse Remodeling in Dilated Cardiomyopathies: Results of the Effects of Beta-Blockers on Remodeling and Gene Expression in the Failing Human Heart (BORG) Trial (NCT01798992)
Background: We have previously reported that when β-blocking agents produce reverse remodeling on nonischemic dilated cardiomyopathies (NDCMs) they effect a partial reversal of changes in constituents of the classic fetal-adult contractile protein (CP)/natriuretic peptide (NP)/SR Ca2+ ATPase (SERCA2a) gene "program". The objective of the current study was to characterize changes in myocardial gene expression among other contractile, signaling, and metabolic pathways that may be associated with reverse remodeling in NDCMs.
Methods and Results: We measured the mRNA expression of 50 genes by quantitative PCR in RNA derived from RV septal endomyocardial biopsies done at baseline and after 3 and 12 months of β-blocker treatment. Forty-seven NDCM patients (mean baseline LVEFs 24+9%, RVEFs 27+9%) were randomized to metoprolol CR/XL, metoprolol + doxazosin, or carvedilol for 18 months, and myocardial gene expression was measured at baseline and after 3 and 12 months of treatment. Thirty-seven patients had reverse remodeling responses by 12 months, defined by change in LVEF (n=30, Δ=23±9%) and/or RVEF (n=28, Δ=16±2%). Previously described decreases in ANP, BNP and increases in α-MHC, SERCA2a, PLN, and RYR2 were again associated with reverse remodeling. In addition, increases in α1A-AR, β1-AR, VLC1, and m-CPT1 were associated with LVEF response, increases in α1A-AR, AT-1R and decreases in β-ARK1, PKC-β, HxK2 and IL-6 were associated with RVEF response, and increases in α1A-AR and AT-1R and decreases in ACTA1, prepro-ET, IL-6, and NHE-1 were associated with biventricular response compared to non-responders.
Conclusions: In addition to previously described changes in CP, NP, and SERCA2a myocardial gene expression, a number of additional calcium handling, sarcomeric, neurohormonal, adrenergic signaling, and metabolic genes are associated with ventricular reverse remodeling. These additional genes may provide further insight into the primary regulatory mechanisms involved in β-blocker mediated reverse remodeling.
- © 2013 by American Heart Association, Inc.